Chronic cannabinoid exposure produces tolerance to the dopamine releasing effects of WIN 55,212-2 and heroin in adult male rats

Neuropharmacology. 2021 Jan:182:108374. doi: 10.1016/j.neuropharm.2020.108374. Epub 2020 Oct 25.


Synthetic cannabinoids were introduced into recreational drug culture in 2008 and quickly became one of the most commonly abused drugs in the United States. The neurobiological consequences resulting from synthetic cannabinoid repeated exposure remain poorly understood. It is possible that a blunted dopamine (DA) response may lead drug users to consume larger quantities to compensate for this form of neurochemical tolerance. Because the endogenous cannabinoid and opioid systems exhibit considerable cross-talk and cross-tolerance frequently develops following repeated exposure to either opioids or cannabinoids, there is interest in investigating whether a history of synthetic cannabinoid exposure influences the ability of heroin to increase DA release. To test the effects of chronic cannabinoid exposure on cannabinoid- and heroin-evoked DA release, male adult rats were treated with either vehicle or a synthetic cannabinoid (WIN55-212-2; WIN) using an intravenous (IV) dose escalation regimen (0.2-0.8 mg/kg IV over 9 treatments). As predicted, WIN-treated rats showed a rightward shift in the dose-response relationship across all behavioral/physiological measures when compared to vehicle-treated controls. Then, using fast-scan cyclic voltammetry to measure changes in the frequency of transient DA events in the nucleus accumbens shell of awake and freely-moving rats, it was observed that the DA releasing effects of both WIN and heroin were significantly reduced in male rats with a pharmacological history of cannabinoid exposure. These results demonstrate that repeated exposure to the synthetic cannabinoid WIN can produce tolerance to its DA releasing effects and cross-tolerance to the DA releasing effects of heroin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Age Factors
  • Analgesics
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Benzoxazines / pharmacology*
  • Cannabinoids / administration & dosage*
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Tolerance / physiology*
  • Heroin / pharmacology*
  • Male
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Pain Measurement / drug effects
  • Pain Measurement / methods
  • Rats
  • Rats, Long-Evans


  • Analgesics
  • Analgesics, Opioid
  • Benzoxazines
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Heroin
  • Dopamine